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Journal of Bacteriology, February 2009, p. 1132-1142, Vol. 191, No. 4
0021-9193/09/$08.00+0     doi:10.1128/JB.01359-07
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Mycobacterium avium Genes MAV_5138 and MAV_3679 Are Transcriptional Regulators That Play a Role in Invasion of Epithelial Cells, in Part by Their Regulation of CipA, a Putative Surface Protein Interacting with Host Cell Signaling Pathways{triangledown}

Melanie J. Harriff,1,3 Lia Danelishvili,1 Martin Wu,1 Cara Wilder,2 Michael McNamara,1,3 Michael L. Kent,1,2,3 and Luiz E. Bermudez1,2,3*

Department of Biomedical Sciences, College of Veterinary Medicine, Oregon State University, Corvallis, Oregon 97331,1 Department of Microbiology, Oregon State University, Corvallis, Oregon 97331,2 Molecular and Cellular Biology Program, Center for Gene Research and Biotechnology, Oregon State University, Corvallis, Oregon 973313

Received 20 August 2007/ Accepted 20 November 2008

The Mycobacterium avium complex (MAC) is an important group of opportunistic pathogens for birds, cattle, swine, and immunosuppressed humans. Although invasion of epithelial cells lining the intestine is the chief point of entry for these organisms, little is known about the mechanisms by which members of the MAC are taken up by these cells. Studies with M. avium have shown that cytoskeletal rearrangement via activation of the small G-protein Cdc42 is involved and that this activation is regulated in part by the M. avium fadD2 gene. The fadD2 gene indirectly regulates a number of genes upon exposure to HEp-2 cells, including transcriptional regulators, membrane proteins, and secreted proteins. Overexpression of two fadD2-associated regulators (MAV_5138 and MAV_3679) led to increased invasion of HEp-2 cells, as well as altered expression of other genes. The protein product of one of the regulated genes, named CipA, has domains that resemble the PXXP motif of human Piccolo proteins, which bind SH3 domains in proteins involved in the scaffold complex formed during cytoskeletal rearrangement. Although CipA was not detected in the cytoplasm of HEp-2 cells exposed to M. avium, the recombinant protein was shown to be potentially expressed on the surface of Mycobacterium smegmatis incubated with HEp-2 cells and, possibly, to interact with human Cdc42. The interaction was then confirmed by showing that CipA activates Cdc42. These results suggest that members of the M. avium complex have a novel mechanism for activating cytoskeletal rearrangement, prompting uptake by host epithelial cells, and that this mechanism is regulated in part by fadD2, MAV_5138, and MAV_3679.

* Corresponding author. Mailing address: Department of Biomedical Sciences, College of Veterinary Medicine, 105 Magruder, Oregon State University, Corvallis, OR 97331. Phone: (541) 737-6538. Fax: (541) 737-2730. E-mail: luiz.bermudez{at}oregonstate.edu

{triangledown} Published ahead of print on 5 December 2008.

Journal of Bacteriology, February 2009, p. 1132-1142, Vol. 191, No. 4
0021-9193/09/$08.00+0     doi:10.1128/JB.01359-07
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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